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Aniline-derived ligands for the thyroid receptor

a thyroid receptor and ligand technology, applied in the field of compounds, can solve the problems of limited development of thyroid agonists and antagonists for treatment, weight gain, and slow discovery and development of new specific drugs to improve the treatment of hyperthyroidism and hypothyroidism

Inactive Publication Date: 2006-09-19
KARO BIO AB
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides compounds that can act as thyroid receptor ligands and can be used to treat diseases associated with metabolism dysfunction or which are dependent upon the expression of a T3 regulated gene. These compounds have a specific formula and can be administered in a therapeutically effective amount. The compounds can be used as agonists for the thyroid hormone receptor-beta. Examples of these diseases include obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmias, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer as well as glaucoma and congestive heart failure."

Problems solved by technology

While the extensive role of thyroid hormones in regulating metabolism in humans is well recognized, the discovery and development of new specific drugs for improving the treatment of hyperthyroidism and hypothyroidism has been slow.
This has also limited the development of thyroid agonists and antagonists for treatment of other important clinical indications, such as hypercholesterolemia, obesity and cardiac arrhythmias.
Thus, in hypothyroidism there is weight gain, high levels of LDL cholesterol, and depression.
In excess with hyperthyroidism, these hormones lead to weight loss, hypermetabolism, lowering of serum LDL levels, cardiac arrhythmias, heart failure, muscle weakness, bone loss in postmenopausal women, and anxiety.
However, replacement therapy, particularly in older individuals is limited by certain of the deleterious effects of thyroid hormones.
Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism, and in particular by cardiovascular toxicity.

Method used

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  • Aniline-derived ligands for the thyroid receptor
  • Aniline-derived ligands for the thyroid receptor
  • Aniline-derived ligands for the thyroid receptor

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0155]

[0156]The malonic ester 1d (5.180 g, 9.91 mmol) was dissolved in 29.5 mL of methanol and cooled to 0° C. Then 29.7 mL of 1N sodium hydroxide (29.73 mmol, 3 equiv.) was added to the reaction over 5 minutes and the reaction was allowed to warm to room temperature. After 15 minutes, the methanol was removed under vacuum. Then the remaining basic solution was diluted with 29.7 mL of water and cooled in an ice bath. To the basic solution was added 1N hydrochloric acid dropwise until the pH was 1. The resulting white semi-solid was collected on a large fritted funnel. The solid was washed 5 times with cold water, then dried over potassium hydroxide for 3 days in vacuo. The final weight of the title compound was 5.01 g (99% yield). The product gave consistent mass spectral data.

[0157]1H NMR (500 MHz, Acetone-D6, δ): 8.07 (s, 2H), 6.75 (m, 2H), 6.37 (dd, 1H, J=8.8, 3.3 Hz), 3.51 (s, 2H), 3.28 (q, 1H, J=6.5 Hz), 1.17 (d, 6H, J=7.1 Hz) 13C NMR (500 MHz, Methanol-D3, δ): 171.06, 167.36, ...

example 2

[0167]

[0168]To a solution of compound 2d (330 mg, 0.78 mmol) in methyl alcohol (3.9 mL) was added 1N aqueous sodium hydroxide solution (2.3 mL, 2.3 mmol). After 20 minutes, the mixture was concentrated in vacuo to an aqueous solution that was diluted with 3.2 mL of distilled water. The solution was cooled to 0° C. and acidified with 1N HCl dropwise, until the pH was 1. A white precipitate was collected and dried under vacuum over potassium hydroxide for 18 hours to yield 288 mg (74%) of the title compound as a white solid. Proton and carbon NMR, and LC / MS were consistent with the desired product.

EXAMPLE 3

[0169]

3-[[3,5-dichloro-[4-hydroxy-3-(1-methylethyl)phenoxy]-2-methylphenyl]amino]-3-oxopropanoic acid

Compound 3a:

[0170]

[0171]To a solution of 4-amino-2,6-dichloro-3-methylphenol (0.70 g, 3.64 mmol) in anhydrous THF (18 mL) cooled with an ice-water bath was added trifluoroacetic anhydride (0.92 mg, 0.62 mL, 4.39 mmol). The mixture was allowed to warm up to RT. After one hour, the mix...

example 3

[0182]

[0183]To a solution of compound 3d (70 mg, 0.16 mmol) in THF (1.5 mL) was added 1N aqueous lithium hydroxide solution (0.5 mL, 0.5 mmol). After one hour, the mixture was acidified with 1N HCl and then extracted with EtOAc (50 mL). The EtOAc extract was washed with brine (2×20 mL), dried (Na2SO4), filtered and concentrated in vacuo to give 57 mg of slightly yellowish solid. The crude product showed a small trace of impurity so it was purified by preparative reverse-phase HPLC [gradient solvent system, from 50% B:50% A to 0% A:100% B (A=90% H2O / 10% MeOH+0.1% TFA, B=90% MeOH / 10% H2O+0.1% TFA) for 10 min, YMC ODS 20×100 mm column] to give 40 mg (61% ) of the title compound as a white solid.

[0184]1H NMR (500 MHz, CD3OD, δ) 7.59 (s, 1H), 6.67 (d, 1H, J=2.7 Hz), 6.60 (d, 1H, J=8.8 Hz), 6.30 (dd, 1H, J=8.8, 3.3 Hz), 3.50 (s, 2H), 3.23 (m, 1H), 2.34 (s, 3H), 1.16 (d, 6H, J=6.6 Hz) MS ESI− [M−H]−=410, 412, 414 (100:64:10)

EXAMPLE 4

[0185]

4-[[3,5-dichloro-[4-hydroxy-3-(1-methylethyl)phenox...

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Abstract

New thyroid receptor ligands are provided which have the general formulain which:X is —O—, —S—, —CH2—, —CO—, or —NH—;Y is —(CH2)n— where n is an integer from 1 to 5, or cis- or trans-ethylene;R1 is halogen, trifluoromethyl, or alkyl of 1 to 6 carbons or cycloalkyl of 3 to 7 carbons;R2 and R3 are the same or different and are hydrogen, halogen, alkyl of 1 to 4 carbons or cycloalkyl of 3 to 6 carbons, at least one of R2 and R3 being other than hydrogen;R4 is hydrogen or lower alkyl;R5 is hydrogen or lower alkyl;R6 is carboxylic acid, or esters or prodrugs;R7 is hydrogen or an alkanoyl or an aroyl.In addition, a method is provided for preventing, inhibiting or treating a disease associated with metabolism dysfunction or which is dependent upon the expression of a T3 regulated gene, wherein a compound as described above is administered in a therapeutically effective amount. Examples of such diseases associated with metabolism dysfunction or are dependent upon the expression of a T3 regulated gene include obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmias, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer as well as glaucoma, congestive heart failure and skin disorders.

Description

[0001]This application is a Divisional of U.S. patent application Ser. No. 09 / 761,050, filed Jan. 16, 2001 now U.S. Pat. No. 6,800,605 that claim priority from U.S. Provisional Application No. 60 / 183,223, filed Feb. 17, 2000.FIELD OF THE INVENTION[0002]This invention relates to novel compounds which are thyroid receptor ligands, and are preferably selective for the thyroid hormone receptor β, and to methods of preparing such compounds and to methods for using such compounds such as in the regulation of metabolism.BACKGROUND OF THE INVENTION[0003]While the extensive role of thyroid hormones in regulating metabolism in humans is well recognized, the discovery and development of new specific drugs for improving the treatment of hyperthyroidism and hypothyroidism has been slow. This has also limited the development of thyroid agonists and antagonists for treatment of other important clinical indications, such as hypercholesterolemia, obesity and cardiac arrhythmias.[0004]Thyroid hormone...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): C07C37/00A61K45/00A61K31/155A61K31/167A61K31/192A61K31/22A61K31/351A61K31/40A61K31/404A61K31/425A61K31/4418A61K31/59A61K31/64A61K38/26A61K38/28A61K45/06A61P3/00A61P3/04A61P3/06A61P5/14A61P9/04A61P9/06A61P9/10A61P17/00A61P17/02A61P17/06A61P17/10A61P17/16A61P19/10A61P25/24A61P27/06A61P35/00A61P43/00C07C233/25C07C233/27C07C235/74C07C235/76
CPCA61K31/167A61K45/06C07C233/25C07C233/27A61K2300/00A61P17/00A61P17/02A61P17/06A61P17/10A61P17/16A61P19/10A61P25/24A61P27/06A61P3/00A61P3/04A61P35/00A61P3/06A61P43/00A61P5/14A61P5/16A61P9/04A61P9/06A61P9/10C07C235/74
Inventor FRIENDS, TODD J.RYONO, DENIS E.ZHANG, MINSHENG
Owner KARO BIO AB
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